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The aim of this survey was to describe the treatment decision making of expert physicians in when and how to treat patients with AL amyloidosis. Fifty amyloid expert physicians completed the survey. Autologous stem cell transplant (ASCT) was considered the first line therapy, if medically feasible, by 73% of the physicians. Excluding ASCT, cyclophosphamide-bortezomib-dexamethasone regimen was the preferred strategy by 72%. Depending on organ involvement, the goal for treatment was CR for 27–35% and very good partial response (VGPR) for 65–72%. In the absence of organ progression but rising FLC, the factors that most influenced when to reinstitute therapy included: dFLC at diagnosis (35.2%); how sick the patient was at diagnosis (24.1%); and time to FLC rise (18.5%). For patients who achieved CR after first-line, in the presence of cardiac/renal progression, 37/42% of providers would consider starting clone directed therapy without evidence of a clone. These data would imply that the current definitions of hematologic progression do not match clinical judgment, clinical experience and a comprehensive evaluation of patient status. These disparities challenge the ability to design therapeutic trials for patients with relapsed/refractory disease. A consensus statement with the definition and validation of new hematologic progression criteria is required.

Background The clinical utility of a new biomarker should ideally be established in a prospective randomized clinical trial. However, such trials are not always practical. As such, it is common for investigators to identify promising biomarkers using archived specimens and clinical data collected from previously completed therapeutic trials. Simon et al. defined such biomarker studies as prospective–retrospective studies and proposed specific conditions to satisfy for such evaluations to be more than hypothesis generating. One condition they proposed is that archived tissues must be available on a sufficiently large number of patients from the pivotal trials to ensure adequately powered analyses. Purpose The purpose of this article is to provide a new perspective on how to estimate power for assessing the prognostic and predictive values of a single binary biomarker in prospective–retrospective biomarker studies. Computer programs are provided to facilitate the use of these methods in practice. Methods The proposed methods utilize additional information that becomes available during the course of the treatment trial including sample size, accrual time, additional follow-up time, and the observed number of events at time of biomarker analysis. These methods involve solving for the exponential hazard rates that give rise to the event numbers that are consistent with those observed while satisfying other design parameter constraints. Conclusion Simon et al. proposed a new paradigm for biomarker design, conduct, analysis, and evaluation in prospective–retrospective studies that offers a more efficient alternative than fully prospective biomarker studies. As a general rule, they suggest that samples from at least two-thirds of the patients be available for analysis. In this article, I expand on this issue and provide a methodological tool useful for estimating study power in prospective–retrospective biomarker studies. It is my hope that these incremental efforts to improve the quality and statistical rigor in biomarker studies will hasten the introduction of useful tumor biomarkers into clinical practice.

Objective To review the treatment choices of women with complete androgen insensitivity syndrome (CAIS) at a single tertiary centre. Design Retrospective review. Patients Women with CAIS identified from our database. Results The study group comprised 141 women with CAIS. Eleven percent (16/141) of women had gonads in situ, 3 of whom were under workup for gonadectomy. The age of gonadectomy in the remainder 125 women was 17 (0.1–53) years. The most common form of HRT was oral oestrogen or transdermal oestrogen in 80% (113/141). 13/141 (9%) women used vaginal oestrogens alone or together with other forms of HRT. Testosterone preparations had been used by 17% (24/141) of women and were currently used in 10% (14/141). Of those who had used testosterone, 42% (10/24) had chosen not to continue after a therapeutic trial. Conclusions In a clinic offering individualised multidisciplinary care for women with CAIS, we found that the majority of women chose oestrogen-based treatment while a significant minority used testosterone.

In the past, liver cirrhosis was considered an irreversible phenomenon. However, many experimental data have provided evidence of the reversibility of liver fibrosis. Moreover, multiple clinical studies have also shown regression of fibrosis and reversal of cirrhosis on repeated biopsy samples. As various etiologies are associated with liver fibrosis via integrated signaling pathways, a comprehensive understanding of the pathobiology of hepatic fibrogenesis is critical for improving clinical outcomes. Hepatic stellate cells play a central role in hepatic fibrogenesis upon their activation from a quiescent state. Collagen and other extracellular material components from activated hepatic stellate cells are deposited on, and damage, the liver parenchyma and vascular structures. Hence, inactivation of hepatic stellate cells can lead to enhancement of fibrolytic activity and could be a potential target of antifibrotic therapy. In this regard, continued efforts have been made to develop better treatments for underlying liver diseases and antifibrotic agents in multiple clinical and therapeutic trials; the best results may be expected with the integration of such evidence. In this article, we present the underlying mechanisms of fibrosis, current experimental and clinical evidence of the reversibility of liver fibrosis/cirrhosis, and new agents with therapeutic potential for liver fibrosis.

The development of amyloid PET imaging was revolutionary for Alzheimer disease (AD). Enabling the visualization in patients of a hallmark pathologic protein aggregate previously seen only at autopsy, the emergence of amyloid PET radiotracers1 transformed AD clinical research by allowing confirmation of amyloid pathology in clinically suspected AD cases, atypical AD variants, and individuals with suspected mixed etiology and by permitting the tracking of longitudinal change in observational studies and especially therapeutic trials of amyloid-lowering drugs.2 Soon, 18F-labeled radiotracers emerged and eventually achieved clinical approvals, aiding diagnosis and management of patients suspected of having AD.3

The feasibility of acquiring clinically relevant histopathologic information on critical underlying amyloid and tau pathology in Alzheimer disease and related diseases is the reason why therapeutic trials now incorporate PET imaging biomarkers in most studies. Specifically, PET is used to assess

The phase II mongersen (GED-0301) trial produced unparalleled success rates in Crohn's disease and generated much hope for a crippling disease. Unfortunately, the subsequent phase III trial was terminated early because of a lack of efficacy. We discuss the differences in trial design that may have contributed to these disparate findings and how these findings may serve as a lesson in subsequent therapeutic trials in Crohn's disease.

In large multinational clinical therapeutic trials, responses in one region can differ from those in another. This article examines reasons for such differences and suggests criteria for determining whether the differences are real or the play of chance.

Despite progress in the supportive care available for critically ill patients, few advances have been made in the searchfor effective disease-modifying therapeutic options. The fact that many trials in critical care medicine have notidentified a treatment benefit is probably due, in part, to the underlying heterogeneity of critical care syndromes.Numerous approaches have been proposed to divide populations of critically ill patients into more meaningfulsubgroups (subphenotypes), some of which might be more useful than others. Subclassification systems driven byclinical features and biomarkers have been proposed for acute respiratory distress syndrome, sepsis, acute kidneyinjury, and pancreatitis. Identifying the systems that are most useful and biologically meaningful could lead to abetter understanding of the pathophysiology of critical care syndromes and the discovery of new treatment targets,and allow recruitment in future therapeutic trials to focus on predicted responders. This Review discusses proposedsubphenotypes of critical illness syndromes and highlights the issues that will need to be addressed to translatesubphenotypes into clinical practice.

Objectives. Neuroprotective treatment, including citicoline, is a new perspective in glaucoma management, having the role of progression delay. The purpose of the present study was to observe the evolution of the different parameters in patients with glaucoma treated with citicoline. Methods. 22 patients with GPUD were enrolled in the study, and they received oral citicoline in addition to the ocular hypotensive therapy. Investigations were performed at the beginning of the current study, then at 3 months and 6 months, and included, besides full ophthalmologic checkup and IOP determination, optic nerve and RGCs OCT, and visual evoked potentials, pattern and flash. The data we obtained were statistically analyzed with the SPSS (Microsoft) program. Results. The outcomes of the study following VEP wave analysis indicated variations in P100 wave amplitude, but after 6 months period, an increase was found. Also, the P2 wave amplitude recorded statistically insignificant variations. The increase in P2 latency at 6 months was noted as statistically significant. Negative correlations were also met between the thickness of the RGC layer and the P100 latency, but also between the amplitude and the latency of this wave. At 6 months, a positive correlation between the RGC layer and the P100 amplitude was observed. The RNFL thickness at the optical disc had higher values at the 6 months visit, it was statistically significant, and a slight increase in the thickness of the RGC layer between successive visits was noted. These might be an examination artifact because clinically they are not possible. The RNFL thickness showed a positive correlation with the amplitude of P100 and P2 waves. Conclusions. The study of the parameters and their correlations demonstrated that citicoline had positive effects in glaucoma on certain aspects, data confirmed by literature.

The diagnosis of primary central nervous system (CNS) vasculitis is often difficult. There are neither specific clinical features nor a classical clinical course, and no blood or imaging investigations that can confirm the diagnosis. Contrast catheter cerebral angiography is neither specific nor sensitive, yet still underpins the diagnosis in many published studies. Here we describe an approach to its diagnosis, emphasising the importance of obtaining tissue, and present for discussion a new, binary set of diagnostic criteria, dividing cases into only ‘definite’ primary CNS vasculitis, where tissue proof is available, and ‘possible,’ where it is not. We hope that these criteria will be modified and improved by discussion among experts, and that these (improved) criteria may then be adopted and used as the basis for future prospective studies of the clinical features and diagnosis of this difficult and dangerous disorder, particularly for coordinated multicentre therapeutic trials.

The attrition of novel analgesic drugs in the clinic can be attributed in the main to two factors: failure of preclinical research findings translating into human pain conditions, and a drop-off of efficacy between proof-of-concept (i.e., Phase II trials) and pivotal, confirmatory (Phase III trials) testing. In order to enhance the efficiency of the clinical drug evaluation process and determine rapidly whether a potential therapeutic candidate gives pain relief, by modulating central pain neurobiology, we propose a 'pre-proof-of-concept' approach, in which an efficacy assessment is performed in a single individual (N-of-1) using subjective clinical pain assessments supported by objective validated functional neuroimaging measures. Using an N-of-1 + i methodology, clinical- and neuroimaging-based metrics can be quantified under conditions of drug versus placebo or drug versus current standard of care conditions.

In the era before antifibrotic therapy, idiopathic pulmonary fibrosis (IPF), the most common of the idiopathic interstitial pneumonias, had a survival rate of 20 to 30% at 5 years,1 a poorer outcom...

Visually scoring freezing of gait (FOG) from video is increasingly recognized as the gold-standard for assessing FOG severity in Parkinson's disease. Surprisingly, no guidelines exist on how to visually score FOG. Here, I present a free template that can be implemented in open-source software to annotate FOG from video. I provide a user guide on how to implement the template and standardize the scoring of FOG and the percentage of time spent with FOG (% FOG). It is hoped that by disseminating this method investigators will be better able to employ % FOG as an outcome in their studies and therapeutic trials. ispartof: JOURNAL OF PARKINSONS DISEASE vol:9 issue:4 pages:821-824 ispartof: location:Netherlands status: published

Pulmonary arterial hypertension (PAH) is a rare disease that carries a poor prognosis. For 45 years, the definition of pulmonary hypertension (PH) has been a mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg, based on expert opinion. Recent data indicate that the mortality risk starts in the mPAP range of 21–24 mmHg, which has recently been reflected in the World Symposium on PH consensus document defining PH as a mPAP > 20 mmHg. The mortality associated with these lower levels of pulmonary pressures suggests that these values reflect a more advanced disease stage than previously recognized. It is unknown whether interventions targeting patients with mPAP values in the range of 21–24 mmHg in the absence of left ventricular or hypoxic lung disease are of clinical benefit. Here we present historical perspective on the hemodynamic definition of PH, discuss recent epidemiologic data, and outline obstacles to enrolling and evaluating response to therapy in mild PAH patients, as well as potentially useful study designs.

In this review, we explored different ways of controlling the placebo effects in clinical trials and described various factors that may increase/decrease the placebo effect in randomized placebo-controlled trials. These factors can be subdivided into four groups, and while not all factors are effective in every study and under all clinical conditions, they show on the whole that – even under the ideal condition of drug therapy, where blinded placebo provision is much easier and warranted than in, e.g., psychotherapy – many factors need to be controlled to ascertain that the goal of the clinical trials, fair assessment of superiority of the drug over placebo in placebo-controlled trials and fair assessment of non-inferiority of the drug compared to another drug in comparator trials, is reached. Ignorance towards the placebo effect, which was common in the past, is no longer acceptable; instead, it should be the goal of all therapeutic trials to minimize the placebo effect in clinical trials, while utilizing and maximizing it in clinical routine.

Alloantibody toward human leukocyte antigens (HLAs) and blood antigens is a major barrier to successful transplantation. This chapter discusses the current options for transplantation in sensitized renal transplant candidates or those with ABO-incompatible living donors. Specific emphasis is placed on what is known regarding the mechanisms and treatment of both early and late antibody-mediated injury, including the results of some recent therapeutic trials. Finally, current knowledge regarding the mechanism of antibody production in the setting of renal transplantation is outlined, highlighting important gaps in current knowledge in this emerging field.

Recent advances in understanding of the molecular biology of prion diseases and improved clinical diagnostic techniques might allow researchers to think about therapeutic trials in Creutzfeldt-Jakob disease (CJD) patients. Some attempts have been made in the past and various compounds have been tested in single case reports and patient series. Controlled trials are rare. However, in the past few years, it has been demonstrated that clinical trials are feasible. The clinicians might face several specific problems when evaluating the efficacy of the drug in CJD, such as rareness of the disease, lack of appropriate preclinical tests and heterogeneous clinical presentation in humans. These problems have to be carefully addressed in future.

Tarihin her döneminde insan ilaca ihtiyaç duymuş ve gerektiğinde kullanmıştır. Ancak günümüzde adeta ilaçla birlikte yaşamaktadır. Bu nedenle hayatının da vazgeçilmez nesnelerinden biri haline gelmiştir. İlaç, üretim ilişkileri ve teknikleri ile birlikte, gelişmiş ve şekil değiştirmiştir. Endüstri devrimi ile seri üretim ile tanışmıştır. Günümüzde ilaç endüstrisi küresel ölçekte büyümüş ve çeşitlenmiştir. Bu çeşitlenme ile ilaç üretiminde birlikte tekelleşme meydana gelmiştir. Endüstri 4.0 ın getirdiği robot, yapay zeka ve özellikle nano teknoloji gelişmiştir. Bu gelişmeler kimya ve bağlamında ilaç endüstrisini etkilemiş ve geliştirmiştir. Bu gelişmeye rağmen, kişilerin ve ülkelerin sağlık giderleri bütçesinde önemli harcamalara neden olmaktadır. Gelişmiş ülkelerde ilaç araştırmaları ve insan üzerinde yapılan deney ve denemeler katı kurallara bağlanmıştır. Denetimlerde oldukça etkili biçimde yapılmaktadır. Bu nedenle de ilaç şirketleri insan üzerinde deney ve denemeleri, denetim olmayan ve yoksul ülkelerde yapmaktadırlar. Türkiye'de bu ülkeler arasında yer almaktadır. Bunun için ülkemizde de insan üzerinde bilimsel deney ve tedavi amaçlı deneme suçları önem arzetmektedir. Bu bağlamda ceza hukuku kapsamında yetkinliği artıracak hukuki düzenlemeler, denetim sistemleri, tespit edilen suçlarda etkin mücadele yöntemleri planlanmalıdır. Ayrıca insan üzerinde bilimsel deney ve tedavi amaçlı denelemer konusunda tıp ve hukuk çevrelerinin, özellikle de toplumun farkındalığı atırılmalıdır. Çalışma ile ceza hukuk kapsamında ilaç ve insan üzerinde deney ve tedavi denemeleri konusu irdelenmektedir., In every period of history, people needed medicine and used it when necessary. But nowadays, people lives with the medication. For this reason, it has become one of the indispensable objects of peoples' life. Along with the production relations and techniques the drug has been developed and deformed. With industrial revolution, it has met with mass production. Today, the pharmaceutical industry has grown and diversified globally. With this diversification, monopolization has been occurred in the production of drugs. Robots made by means of Industry 4.0, artificial intelligence and especially nano technology has been developed. These developments have influenced and developed the pharmaceutical industry in the context of chemistry. Despite this development, health expenditures of individuals and countries cause significant expenditures in their budget. In developed countries, drug research, experiments and trials on human beings have been rigidly regulated. The audits are done very effectively as well. As a consequence, pharmaceutical companies carry out experiments and trials on human beings in non-controlled and poor countries. Turkey is also among these countries. Therefore, in our country crimes related to scientific experimentation and therapeutic trials applied on human beings are considered to be important. In this context, legal regulations that will increase competence within the scope of criminal law, audit systems, effective combat methods should be planned. In addition, the awareness should be expanded about the scientific experiments and Therapeutic trial on human beings, especially among the society, in the fields of medicine and law. Hereby, drugs experiments and therapeutic trial on human beings in context of criminal law are examined.

The explosion of new retinal imaging technologies and the exponential growth in the size and complexity of retinal imaging datasets has fueled a demand for automated retinal image analysis tools. One disease where image analysis tools are of particular importance is age-related macular degeneration (AMD). Image analysis approaches to identify and quantify atrophy associated with AMD have evolved from semiautomatic approaches requiring extensive manual input to more automated approaches using prespecified or custom-crafted features, to fully automated artificial intelligence (AI) deep learning approaches where image features are learned automatically. In addition, similar approaches appear to be applicable for the automated identification and quantification of risk factors in early/intermediate AMD eyes which may be associated with risk for progression to late AMD. This may allow the design of novel therapeutic trials aimed at intervention early in the disease process.

Many authors suggested that IgA Vasculitis (IgAV) and IgA Nephropathy (IgAN) would be two clinical manifestations of the same disease; in particular, that IgAV would be the systemic form of the IgAN. A limited number of studies have included sufficient children or adults with IgAN or IgAV (with or without nephropathy) and followed long enough to conclude on differences or similarities in terms of clinical, biological or histological presentation, physiopathology, genetics or prognosis. All therapeutic trials available on IgAN excluded patients with vasculitis. IgAV and IgAN could represent different extremities of a continuous spectrum of the same disease. Due to skin rash, patients with IgAV are diagnosed precociously. Conversely, because of the absence of any clinical signs, a renal biopsy is practiced for patients with an IgAN to confirm nephropathy at any time of the evolution of the disease, which could explain the frequent chronic lesions at diagnosis. Nevertheless, the question that remains unsolved is why do patients with IgAN not have skin lesions and some patients with IgAV not have nephropathy? Larger clinical studies are needed, including both diseases, with a common histological classification, and stratified on age and genetic background to assess renal prognosis and therapeutic strategies.

5063 Background: ATM mutations, one of a family of DNA repair defects prevalent in prostate cancer, have been included in a list of actionable mutations for PARP inhibitor (PARPi) therapeutic trials. Despite preclinical evidence, PARPi have shown minimal clinical activity in ATM mutant prostate cancer (ATMmPCa). The present analysis explores co-occurring genomic alterations that may drive outcomes of metastatic PCa (mPCa) patients with tumors harboring ATM mutations and provide clues for understanding therapy resistance and potential targets. Methods: This study included molecular profiling analysis of 1375 cases of mPCa. Tumors were analyzed using next-generation sequencing (NGS), whole transcriptome sequencing (WTS), and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ). dMMR/MSI-H status was determined by IHC, NGS, and fragment analysis and tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations. We performed differential gene expression analysis of HR-associated transcripts such as ATR, PARP1-3, RAD50, RAD51A/B/C/D and RAD54. Significance was determined using the ꭓ2 test and Benjamini-Hochberg method. Results: Fifty-nine (4.2%) cases harbored pathogenic ATM mutations, 84 (6.2%) harbored BRCA2 mutations. 1018 tumors (74%) were deemed homologous recombination proficient (HRP) and 155 tumors (11.3%) were HR Deficient (HRD); harboring one or more mutation in HR-related genes excluding ATM and BRCA2. The mutation rate of TP53 was significantly lower in ATMmPCa (12.0%) compared to BRCA2mPCa (35%), HRD (35%) and HRP (46.6%) tumors. ATMmPCa showed higher rates of SMAD2 (3.7%/1%) and FLCN (5.2%/0.3%) alterations compared to HRP cases. PARP1 and RAD51D gene expression was reduced in ATMmPCa compared to HRP (p < 0.05) and BRCA2mPCa ( p < 0.05) tumors, respectively. No differences in gene expression levels were detected for ATR, PARP2, PARP3, RAD50, and RAD54. Chromosomal segments demonstrating differential CNA in ATMmPCa vs HRP, HRD, or BRCA2mPCa included FGF19, FGF4, PTPN11, ALDH2, DAXX, BCL7A, CCND1, BMPR1A and MEF2B (Q-value < 0.05 determined by ꭓ2). The most common CNA in ATMmPCa was CCND1, present in approximately 13% (7/55) of cases. Compared to BRCA2mPCa and HRD cases, ATMmPCa cases are less likely to display markers of immunotherapy response such as dMMR/MSI-H or TMB ≥10 mutations/MB. Conclusions: ATMmPCa demonstrated several differences in co-occurring alterations compared to BRCA2mPCa, HRD and HRP mPCa. ATMmPCa tumors were less likely to harbor alterations in TP53 compared to BRCA2, HRD or HRP tumors. CNA in ATMmPCa occurred in 9 genes across distinct mPCa molecular subtypes and were enriched for those associated with the 11q13 amplicon harboring Cyclin D1. The FGF and PTPN11 related pathways are potentially targetable pathways in ATMmPC and may merit further study.

Acquired dermal macular hyperpigmentation (ADMH) is an umbrella term that includes disorders clinically characterized by small and large pigmented macules/patches and histopathologically showing an evidence of current or resolved interface dermatitis with pigment incontinence, without clinically significant prior inflammatory phase. The term intends to include diseases previously described in the literature as lichen planus pigmentosus, Riehl's melanosis/pigmented cosmetic dermatitis and ashy dermatosis/erythema dyschromicum perstans. The nomenclature and origin of these disorders have always been a matter of discussion. These disorders share many clinicopathological similarities, are difficult to treat and adversely affect the quality of life. Recent consensus points towards the need for a unifying term to facilitate research and therapeutic trials. This article aims to provide a comprehensive review of the recent advances in ADMH.

For children who stutter (CWS), there is good evidence of the benefits of treatment for pre-school age, but an evidence gap for elementary school age. Here we report on the effectiveness of a fluency shaping treatment for 6- to 9-year-old children. The main treatment component is the reinforcement of soft voice onsets. An intensive in-patient group treatment phase lasts 6 days, followed by a 6-month maintenance phase with 3 in-patient weekend group refresher courses. Child and a parent participate together in various treatment activities. In this controlled intervention study (waitlist control, intention-to-treat design) assessments were performed before treatment (T1), 4 weeks after the intensive phase (T2), at the end of the maintenance phase (T3), and 1 year later (T4). Participants were 119 children (108 boys, 11 girls, age 5.5‑10.4 years). Control conditions included a subgroup with delayed treatment (N=25) as well as the assessment of complexity of utterances, inter-rater reliability, and speech naturalness. From before treatment to 1-year follow-up, percent stuttered syllables and OASES-S (Overall Assessment of the Speaker's Experience with Stuttering - School-age) scores decreased with large effect size. Speech naturalness improved during this period but did not reach the level of non-stuttering children. Complexity of utterances increased during the intensive phase, but only temporarily. Twenty children (16.8 %, including dropouts) showed no demonstrable treatment benefit. Fluency shaping treatment can be effectively applied to young school children. It is assumed that parental support, group therapy, intensive treatment, and regular exercises at home are essential.

We present a rare case of Coombs-negative autoimmune haemolytic anaemia in a multiparous woman in secondary care. There were no known underlying medical or obstetric risk factors for haemolytic anaemia. Following extensive investigation and a therapeutic trial of oral corticosteroids, a diagnosis was made. Autoimmune haemolytic anaemia is potentially fatal, and prompt diagnosis with haematology input is essential to ensure maternal and fetal safety in pregnancy and the puerperium. With only a small number of cases of Coombs-negative autoimmune haemolytic anaemia reported in the literature, we present this rare case for discussion. We highlight the importance of thorough investigation of refractory anaemia in pregnancy and consider the associated challenges., Highlights • Anaemia is pregnancy is common. • Refractory anaemia should be thoroughly investigated, it can be associated with increased maternal morbidity and mortality. • Coombs negative anaemia in pregnancy is rare • We report a case report of Coombs negative anaemia in pregnancy, with no significant underlying medical or family history.

Background Short-lasting unilateral neuralgiform headache attacks (SUNA) is a primary headache characterized by frequent attacks of severe headaches in association with ipsilateral cranial autonomic features. SUNA is defined as a strictly unilateral pain and bilateral cases are very unusual, so secondary causes should be searched for vigorously if there are bilateral symptoms. Despite a number of therapeutic trials, effective management for the majority of SUNA patients is not available at present. Management of SUNA is often difficult. Case We report the case of a young boy with bilateral SUNA attacks, with no detected underlying cause, who is responsive to indomethacin. Conclusion Rarely, primary SUNA can present with bilateral symptoms. According to our experience in this case, indomethacin should always be offered to patients with suspected SUNA.

To assess the sensitivity and specificity of the Awaji and revised El Escorial diagnostic criteria (rEEC) in amyotrophic lateral sclerosis (ALS).We conducted a large prospective multicenter study, recruiting 416 patients (253 male, 163 female) between January 1, 2012, and August 31, 2015, to compare the diagnostic accuracy of Awaji and rEEC in accordance with standards of reporting of diagnostic accuracy criteria.The sensitivity of the Awaji criteria (57%, 50.0%-63.3%) was higher when compared to rEEC (45%, 38.7%-51.7%, p0.001), translating to a 12% gain in sensitivity. The specificity of the both criteria were identical, 99.5%, indicating the number needed to test in order to diagnose one extra case of ALS was 1.8 (1.5-2) for Awaji criteria and 2.4 (2-2.6) for rEEC. The Awaji criteria exhibited a higher sensitivity across subgroups, including bulbar (p0.001) and limb-onset (p0.001) patients. The inclusion of the possible diagnostic category as a positive finding enhanced sensitivity of the Awaji criteria and rEEC, particularly in early stages of ALS, while maintaining specificity.The present study established a higher sensitivity of Awaji criteria when compared to rEEC, with diagnostic benefits evident in bulbar and limb-onset disease. Inclusion of possible as a positive finding enhanced sensitivity of both criteria, while maintaining specificity, and should be considered in clinical practice and future therapeutic trials.This study provides Class IV evidence that the Awaji criteria have a higher sensitivity and the same specificity as the rEEC in identifying patients with ALS.

Pediatric brain tumors are the leading cause of cancer-related death during childhood. Since the first pediatric brain tumor clinical trials, the field has seen improved outcomes in some, but not all tumor types. In the past few decades, a number of promising new therapeutic agents have emerged, yet only a few of these agents have been incorporated into clinical trials for pediatric brain tumors. In this review, the authors discuss the process of and challenges in pediatric clinical trial design; this will allow for highly efficient and effective clinical trials with appropriate endpoints to ensure rapid and safe investigation of novel therapeutics for children with brain tumors.

Background: Molluscum contagiosum is a common self-limiting viral infection of the skin. Many therapeutic agents have been used with varying success rates. Objective: To evaluate and compare the effectiveness of topical 10% KOH solution and 25% podophyllin solution as home-based treatments of molluscum contagiosum. Patients and methods: This open randomized comparative therapeutic trial was conducted in the department of dermatology, Al-Yarmouk Teaching Hospital, Baghdad, Iraq between January and October 2015. The patients were divided randomly into two equal groups. Group A patients were treated with 10% KOH solution and those in group B with 25% podophyllin solution. All patients were assessed weekly for 4 weeks for therapeutic response. Results: Fifty-two patients (age: 2–34 years) with MC were enrolled in this study, 25 patients in group A and 20 patients in group B completed the study. Sixteen (64%) patients in group A showed complete clearance of lesions versus 14 (70%) patients in group B. No systemic side effects were reported in both groups and the local side effects were comparable between both groups. Conclusion: Both 10% KOH solution and 25% podophyllin solution are effective local therapies for the treatment of MC with comparable success rates (64% and 70% respectively).

Primary perniosis is an annoying cold-induced dermatosis. Many therapeutic agents have been tried with either unsatisfactory or controversial results. The aim of this study was to assess the efficacy of oral pentoxyfylline in the treatment of primary perniosis. A double-blind placebo-controlled randomized therapeutic study conducted in dermatology department of Al-Yarmouk Teaching Hospital, Baghdad, Iraq during four winter seasons between 2010 and 2014. The patients were randomly allocated into two equal groups: group A patients were given oral pentoxyfylline 400 mg thrice daily whereas patients in group B were given an identical placebo tablet thrice daily for 3 weeks. Therapeutic response of both groups was clinically assessed weekly for 3 weeks and side-effects were recorded. A total of 110 patients with chilblains completed this therapeutic trial. The mean age was 24.98 ± 9.17 year. Male to female ratio was 1:2.4. All patients presented with erythematous papules, plaques or nodules. Very good therapeutic response was significantly better for group A than that of group B at 7th, 4th, and 21st days of the trial (p-value: 0.0148, 0.0000004, and 0.0000000, respectively). No side effects were encountered in both groups. Pentoxyfylline is an effective and safe drug for treatment of primary perniosis.

Background Infarct growth (IG) is used as surrogate end-point in therapeutic trials. For practical reasons, infarct growth is commonly assessed using simple subtraction of acute from follow-up diffusion-weighted imaging (DWI) lesion volumes. However, the volume subtraction method will underestimate true infarct growth in case of diffusion-weighted imaging lesion reversal. Aim To measure the size of the difference between true infarct growth on voxel-based coregistration and infarct growth approximated with simple volume subtraction. Methods We retrospectively analyzed 322 consecutive stroke patients (median (IQR) age: 70 years (57–80), National Institute of Health Stroke Score at admission 14 (8–19)), who underwent a magnetic resonance imaging before (DWI1) and ≈24 h (DWI2) after IV-thrombolysis. IGvoxel-based was defined as the volume of signal changes on DWI2 that did not overlap with that on coregistered DWI1. This was compared with simply subtracting DWI1 from DWI2 lesion volume (IGsubtracted). We also compared these two metrics for the prediction of three-month unfavorable outcome (mRS ≥ 2) using c-statistics of multivariable models, adjusted for age, and National Institute of Health Stroke Score. Results Infarct growth volume metrics were strongly correlated (ρ = 0.94), but IGsubtracted substantially underestimated IGvoxel-based (median (IQR): 9.52 (0.23–38.9) vs. 16.98 (4.4–45.4) mL). Of the 75 patients with shrinking or stable diffusion-weighted imaging lesion using volume subtraction, IGvoxel-based was ≥5 mL in 20 (27% of the subset, 6.2% of the whole population). Moreover, IGvoxel-based better predicted unfavorable outcome than IGsubtracted (c-statistics = 0.86 (95% CI, 0.82–0.90) vs. 0.82 (0.78–0.87), P = 0.003). Conclusion At early post-thrombolysis time points, the simple subtraction of lesion volumes masked substantial diffusion-weighted imaging lesion growth in 6.2% of patients. Although more time-consuming, the voxel-based method may impact results of trials that use infarct growth attenuation as an end-point.

Adrenocortical carcinoma (ACC) is a rare and complex disease associated with a high mortality rate. Despite intensive translational and clinical research, prognosis remains poor. Over the past decade, a significant effort has been made to develop multinational, collaborative studies to better understand the pathogenesis and clinical features of this rare disease in attempt to improve the therapeutic strategies and patient outcome. The results of both standard and newer treatments are discussed in this review as well as the recent discovery of pathways involved in ACC pathogenesis that provide the rationale to introduce new molecular target therapies. Finally, remaining issues regarding how to improve available therapies in adjuvant setting are raised and addressed.

Multiple cerebral tuberculomas complicating miliary tuberculosis are a rare occurrence. It is rarer still for multiple cerebral tuberculomas to present without focal neurological deficits. We report the case of a middle-aged Nigerian male with the co-morbidity of miliary tuberculosis and multiple cerebral tuberculomaswho presented without focal neurological deficits buthad complete resolution of symptoms and signs following a 6-month course of antituberculous therapy. This unique case emphasizes the need for a high index of suspicion in the diagnosis of atypical presentations of cerebral tuberculomas while also further illustrating the place of computed tomographic scan of the brain in diagnosis. The case also illustrates the place of therapeutic trial in management.

A tinha incógnita é causada pela modificação de uma dermatofitose após tratamento com imunossupressores, geralmente corticoides tópicos, mascarando as suas características típicas, resultando na progressão da infecção fúngica original. Relata-se um caso clínico de um homem de 71 anos que desenvolveu um quadro de “picadelas” (sic), dor e desconforto no antebraço direito associado a lesões pápulo-vesiculares de cor rósea, não pruriginosas. O doente foi avaliado e medicado, com antiviral, antibiótico, anti-inflamatório não esteroide e corticoide sem sucesso, tendo desenvolvido lesões pápulo-pustulosas violáceas com descamação em cerca de 1 mês. Após prova terapêutica com um agente antifúngico e depois de descoberto que o paciente usava cronicamente corticoides tópicos, foi diagnosticada uma tinha incógnita. O diagnóstico da tinha incógnita representa um desafio para o Médico de Família, uma vez que esta mimetiza várias condições dermatológicas.

Objectives We sought to determine the speed at which patients were accrued into published phase III oncology trials across geographic locations and to identify the factors that may influence this process. Materials and methods We searched OVID-Medline and identified all phase III oncology therapeutic trials published in 2006 to 2010. The speed of accrual for each trial was calculated by dividing the number of patients enrolled by the number of months the trial was open (patients/mo). Results Five hundred forty-six trials were included in our study. Most of the trials were for adults (96%), late-stage cancers (78%), sponsored by either cooperative groups or academic centers (66%), and had negative results (58%). The most common trial locations were multinational (45%), United States (16%), Italy (7%), Germany (6%), Japan (6%), and France (5%). Compared with trials conducted in a single country, multinational trials accrued significantly more patients per trial, completed enrollment faster, and were published sooner (all P≤0.01). Multivariate analyses showed that multinational (P=0.001), breast cancer (P=0.001), industry sponsored (P=0.001), and equivalency trials (P=0.039) accrued significantly faster than other types of trials. Placebo-controlled and non-placebo-controlled trials accrued at similar speeds. We found no difference in speed of accrual between the United States and Europe. Conclusions Speed of accrual for phase III oncology trials is fastest among multinational trials and independently influenced by the type of trial sponsor, cancer investigated, and study outcome, but not by placebo use. Trials conducted in single countries seem to accrue at similar speeds.